DESCRIPTION (Applicant's Description): Society's reluctance to accept the importance of our body's circadian clock has resulted in maladies ranging from jet lag to tragic, fatigue-induced commercial accidents. Administration of drugs with no regard to the time of day can result in widely variable drug efficacy and capricious tolerance of side effects. Several psychiatric and sleep disorders have been attributed to a dysfunctional circadian system. A better understanding of how the circadian clock is regulated and synchronized to the environment will lead to phototherapeutic and pharmacologic strategies to address these "chronopathologies." Light detected through the eyes is the primary agent responsible for synchronizing the mammalian circadian clock to the environment. Paradoxically, the only known photoreceptors in retina (the rods and cones) are not required for this synchronizing effect of light. Animals lacking rods and cones continue to regulate their circadian systems normally. These data suggest that a non-rod, non-cone class of photoreceptor must exist within the mammalian eye. We have identified a novel human and mouse opsin, melanopsin, that is similar to the rod and cone opsin photopigments. Melanopsin is not localized to rods or cones, but rather to very few cells within the ganglion cell layer of the mouse inner retina. Interestingly, this unique distribution is identical to the distribution of ganglion cells known to project to the hypothalamic suprachiasmatic nuclei (SCN), the central circadian oscillator of mammals. These melanopsin-containing cells are the best candidate circadian photoreceptors known to date. The central hypothesis of this application is that melanopsin is required for normal photic regulation of circadian rhythms in mammals. To test this hypothesis, we will determine the spectral absorption profile of heterologously expressed mouse melanopsin to see if it matches the known spectral sensitivity of the murine circadian system. We will determine if melanopsin is localized in ganglion cells labeled by retrograde neuronal tract tracers originating in the SCN. Finally, we will assay the circadian photosensitivity of mice lacking functional melanopsin. Successful completion of these aims will give us a better understanding of melanopsin's role in the photoregulation of circadian rhythms. Confirmation of melanopsin's involvement in circadian rhythm regulation will provide a therapeutic "entry point" for the treatment of circadian disorders.